SCIENCE & TECHNOLOGY

CANCER'S TOLL ON THE BRAIN Chemotherapy may impair cognitive abilities, but remedies are under development

FIGHTING Melanie Orndoff receives chemotherapy for leukemia.

Known informally as chemobrain or chemofog, this condition can make it hard to find the right word during a con­versation or to learn new material. People suffering from chemobrain may "have to read the same page of material over and over again," according to Tim A. Ahles, a psychologist who is a professor of psychia­try and program director of the Center for Psycho-Oncology Research at Dart­mouth Medical School. They may have difficulty finding their keys or remember­ing what they meant to buy at a store. The speed at which they process information may drop.

Compared with the cognitive effects of conditions such as Alzheimer's disease, Ahles notes, the mental changes accom­panying chemobrain "are relatively subtle. But they still can be very disruptive and interfere with achieving work or educa­tional goals."

The changes that characterize chemo­brain have proven hard to spot in standard­ized tests of memory and attention. Pa­tients who experience cognitive changes after chemotherapy often score in the nor-

SOPHIE L. ROVNER, C&EN WASHINGTON

WHEN SHE WAS TREATED for breast cancer in 2003, Janet B. suffered the typi­cal side effects of chemo­therapy: nausea, fatigue,

and hair loss. Subsequent radiation treat­ments barely fazed her, apart from causing some additional fatigue. But after her cancer treatment ended, when she was struggling to regain her strength, she no­ticed another problem.

Her short-term memory was shot. "I'd always been a little absent-minded," she says, "but that got a lot worse. If I start a load of laundry and the phone rings, I'll forget I was doing laundry and I'll go do something else." Janet also finds it harder to concentrate now. "I'm more distract-ible," she explains. "It's like suddenly I have attention deficit disorder."

Janet's sense of direction is no longer re­

liable. Nor can she plot a driving route in her head anymore. "Sometimes when driv­ing in a familiar area, I get a little disori­ented and can't visualize what landmarks are coming next," she says. "It's not like I'm totally lost, but I have to think about it more."

Despite the side effects, Janet is delight­ed with the success ofher cancer treatment. But patients, physicians, and biomedical researchers are increasingly asking what price patients pay for beating cancer with this type of treatment.

Chemotherapy, though life-saving, may itself cause cancer later in life. The treat­ment may also cause other persistent prob­lems such as hearing loss, heart damage, and infertility. And evidence is building that chemotherapy can lead to difficulties with memory and concentration, much like those Janet has experienced.

•HCI

OCH,

DUAL PURPOSE Ritalin, which is typically used to treat attention deficit hyperactivity disorder, might also have some utility in chemobrain cases.

mal range in these tests. Unfortunately, such tests are usually administered only after chemotherapy treatment, so changes in an individual's test results are rarely de­termined. Even when pretreatment tests are conducted, however, it's not easy to in­terpret the results because the period prior to treatment is so stressful.

Christina A. Meyers, a neuropsycholo­gist at the University of Texas M. D. An­derson Cancer Center, is one of the few

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SCIENCE & TECHNOLOGY

researchers who have collected data on patients prior to treatment. She has found evidence that patients with hematologic, lung, or breast cancer showed learning and memory problems before starting chemotherapy. Among the breast cancer patients, che­motherapy nearly doubled the pretreatment percentage of patients suffering from cogni­tive difficulties, though half of them improved within a year of treatment.

IT'S POSSIBLE that an in­flammatory immune response caused by cancer itself and/or by cancer treatment may be re­sponsible for some of these cas­es of chemobrain, according to Meyers. The immune system is regulated by proteins known as cytokines, which are secreted by immune cells. Cytokines are activated in response to infec­tion or injury and cause brain-mediated symptoms, including fatigue, lack of motivation and appetite, sleep disturbance, and problems with concentration. "Certain cancers and cancer treatments secrete or induce cytokines, which may be one mechanism by which cancer-related symptoms, including cogni­tive impairment, develop," Meyers says.

For instance, Meyers found that pa­tients with acute leukemia had elevated levels of certain cytokines circulating in their blood, which correlated with the ex­tent of their cognitive impairment and fa­tigue. This finding lends some support to the hypothesis that chemobrain may be due at least in part to cytokine activation of the immune system, Meyers says. Con­ceivably, anti-inflammatory drugs might be useful as an antidote to the harmful

der development and may also help. Such treatments would have to be used with cau­tion so as not to suppress beneficial im­mune activity.

Carmustine

NEUROTOXIC Chemotherapy agents carmustine and cisplatin—along with methotrexate and cytarabine—can damage myelin in the brain.

activity of cytokines, she adds. Cytokine antagonists—-which prevent the binding of cytokines to their target cells in the immune system and elsewhere—are un-

SYMPATHETIC Although the cognitive changes wrought by chemobrain aren't as severe as those in Alzheimer's patients, Ahles says, they can nevertheless interfere with work and educational goals.

Several other factors can contribute to cognitive difficulties experienced by che-motherapypatients.Duringchemotherapy and shortly thereafter, "almost everybody reports having problems with memory and concentration," Ahles says. Patients are "anemic, they're nauseous, they're taking medications that are sedating, and they're not sleeping well. There's a whole lot of reasons why they could be experiencing cognitive problems."

Some people continue to experience fa­tigue or sleep disruption after chemother­apy. Others battle depression and anxiety. Some patients continue to take medica­

tion after chemotherapy, either to hold cancer at bay or to treat other conditions. "If you treat the fatigue or depression or you change the dose of a sedating medication, very often the cog­nitive problems will resolve," Ahles said during a June 2004 workshop on chemobrain. The workshop was hosted by Cancer-Care, an organization that pro­vides counseling and educational services related to cancer.

Other potentially reversible sources of cognitive problems include vitamin B-12 and folic acid deficiency or an underactive thyroid, according to Stewart Fleishman,

Cisplatin

another workshop speaker. Fleishman is director of cancer supportive services at Continuum Cancer Centers of New York: Beth Israel Medical Center. Hormonal

changes that can occur with cancer or its treatment can also play a role, he added.

As breast cancer patient Ja­net, who was 51 when she had cancer treatment two years ago, sums it up: "I can see lots of differences in cognitive processes since chemo. It's hard to know what is chemo related and what is just to be expected at this age."

Whatever the basis for their cognitive difficulties, most patients report a grad­ual improvement within six months to a year or two after treatment. "However, there is agroup of people who say they improve to a certain extent and then hit aplateau and nev­er improve after that," Ahles says. "We don't know how big that group is, but it's probably in the 20-25% range."

Furthermore, the source of their ongoing cognitive prob­

lems is uncertain. Chemotherapy may af­fect the brain directly, or it may alter some other aspect of human biology. "Those are the kinds of things that we are intensively trying to study right now," Ahles says. "If we can understand the cause of chemo­brain, then hopefully we can come up with ways of either treating it or, ideally, pre­venting the problem."

One fundamental question that needs to be answered is whether chemotherapy drugs get into the brain. Traditionally, pas­sage of chemotherapy drugs into the brain was believed to be blocked by the blood-brain barrier, according to the Mayo Clin­ic. But some researchers now suspect that some of these drugs slip past.

Once they're in the brain, chemothera­py drugs could cause atrophy of gray mat­ter and demyelination of white matter fi­bers, Ahles says. The compounds may also alter neurotransmitter levels.

ANOTHER HYPOTHESIS is that chemo therapy drugs cause vascular injury in the brain and perhaps elsewhere. It's also pos­sible that the free radicals produced by che­motherapy to kill cancer cells also harm membranes and DNA of normal cells.

There are still many unknowns, ac­cording to the Mayo Clinic. Which che­motherapy drugs are more likely to cause

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memory changes? Do higher doses pose a bigger risk than do smaller ones? And who is more likely to suffer from cognitive im­pairment after chemotherapy?

The answer to that last question is like­ly to be multifaceted, but genetics might be involved. For instance, Ahles suspects that a gene associated with Alzheimer's disease may increase a patient's vulnerabil­ity to chemobrain. He has collected pre­liminary data showing that patients who have the e4 allele of the apolipoprotein E (APOE) gene score worse on cognitive tests than patients with other forms of the gene. Ahles is now conducting a more in-depth study of APOE and other genetic markers "to see if we can begin to predict who might be at higher risk for developing some of these cognitive problems."

Two factors may explain the e4 allele's influence: It diminishes the body's abil­ity to repair the vascular and nervous sys­tems after they have been damaged, and it is associated with a smaller than average hippocampus, a brain region involved in memory and concentration.

Another population that may be par­ticularly vulnerable to the negative con­

sequences of chemotherapy comprises children, adolescents, and young adults, because their brains are still developing.

The Children's Oncology Group, a can­cer research organization, notes that high doses of both methotrexate and cytara­bine are associated with cognitive deficits such as diminished IQ, processing speed, and memory when administered to girls under the age of three. Methotrexate and cytarabine are both antimetabolites, com­pounds that block enzymes that cancer cells need to survive. An antimetabolite prevents the cancer cells' growth and even­tually causes them to die.

But these two compounds—in addition to others such as carmustine and cisplat-in—can cause toxic leukoencephalopathy, in which myelin in cerebral white matter is damaged, according to Robert E. Smith, codirector of the South Carolina Cancer Center (J. Support. Oncol. 2004,2,39).

While research is ongoing into the causes of chemobrain, scientists are also hunting for potential treatments.

For instance, three weeks of treatment with Ritalin (methylphenidate hydrochlo­ride) has been shown to help children who develop attention and learning problems as a result of chemotherapy, Raymond K. Mulhern and colleagues reported last De­cember (J. Clin. Oncol. 2004,22, 4795). Mulhern, who died this year, was chief of behavioral medicine at St. Jude Children's Research Hospital. Ritalin is usually pre­scribed for the treatment of children with attention deficit hyperactivity disorder (ADHD). The drug is a central nervous system stimulant that blocks reuptake of the neurotransmitters norepinephrine and dopamine.

Meanwhile, Fleishman has been in­volved in a recent multicenter trial of

the Celgene drug Focalin, which is dexmethylpheni-date, the R,R enantiomer of racemic Ritalin. Adult pa­tients enrolled in the trial had received chemotherapy ending at least two months before their participation in the study began. They had to have fatigue and problems with memory or concentration but not have anemia. The patients giv­en Focalin—who had been treated for breast or ovar­ian cancer—showed im­provements in memory and fatigue compared with pa­tients who received a place­bo. The results of this study

were presented at the American Society of Clinical Oncology meeting this June.

Other medications that may be useful to assess include anti-inflammatory drugs and antidepressants such as Zoloft (sertra­line hydrochloride) and Prozac (fluoxetine hydrochloride), according to Fleishman.

Other drugs that are being considered include erythropoietic agents, which have traditionally been used to combat the ane­mia and associated fatigue that are com­mon in cancer patients. Like the natural hormone erythropoietin, these agents bind to receptors on the surface of erythroid progenitor cells, which then mature into

Zoloft

WORTH A LOOK Antidepressants Zoloft and Prozac might alleviate chemobrain symptoms.

red blood cells. Researchers have discov­ered, however, that erythropoietin recep­tors can be found on other cells, including neuronal cells, Smith says. Furthermore, erythropoietin demonstrates neuropro­tective abilities, possibly by increasingpro-duction of antiapoptotic proteins.

THESE FINDINGS may explain why some evidence suggests that erythropoi­etic agents have cognitive benefits. For instance, a pilot study showed that treat­ment with epoetin alfa during anthracy-cline-based chemotherapy eased cogni­tive impairment in breast cancer patients, according to Baylor University oncologist Joyce A. O'Shaughnessy and colleagues {Clin. Breast Cancer 2005,5,439).

It's not yet clear whether neuroprotec­tion or enhanced tissue oxygenation result­ing from increased blood cell production is responsible for the cognitive improvement that results from treatment with erythro­poietic agents, Smith notes. These agents will have to be studied carefully because they may contribute to tumor growth.

Patients can also turn to a number of nonpharmacological approaches to man­age chemobrain, Meyers notes. Options include exercise, behavioral interventions such as relaxation therapy, and compensa­tory strategies such as making to-do lists.

Cancer therapy has evolved to a point where patients and physicians can increas­ingly take into account the nature of life after treatment. Both physicians and re­searchers are working to lessen the burden of surviving cancer. As Meyers puts it, "Op­timizing the quality of life of cancer pa­tients is possible, essential, and should be on equal footing with anticancer therapy." •

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Prozac

Cytarabine

RISKY FOR GIRLS When used to treat cancer in young girls, high doses of methotrexate or cytarabine can cause cognitive problems including diminished IQ, processing speed, and memory.

Methotrexate